Voxelotor Improves Cerebral Hemodynamic Parameters in Pediatric Sickle Cell Disease

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Voxelotor decreases oxygen extraction fraction and cerebral blood flow towards levels observed in healthy children.

According to new research, voxelotor significantly decreases oxygen extraction fraction (OEF) and cerebral blood flow among children with sickle cell disease (SCD), similar to levels seen in healthy children.1

The study used non-invasive frequency-domain near-infrared spectroscopy (FDNIRS) combined with diffuse correlation spectroscopy (DCS) to assess regional OEF, cerebral blood volume (CBV), and cerebral blood flow (CBF) in children with sickle cell anemia (SCA). Improvements in these parameters were observable at 4 weeks and persisted until the study's end at 12 weeks.

“Given that previous work has shown that these parameters are elevated in children with sickle cell anemia compared to healthy controls, these results suggest that voxelotor may reduce cerebral hemodynamic impairments,” wrote the investigative team led by Erin M. Buckley, PhD, Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University.

Evidence has shown chronic elevations of cerebral blood flow in SCD compensate for oxygen delivery decreases caused by severe anemia.2 Both cerebral blood flow and OEF are hypothesized to leave patients with SCA unprepared to respond to acute increases in oxygen metabolic demand. OEF elevations have been linked to an increased risk of infarction, which poses a significant effect on neurological morbidity and quality of life.

An inhibitor of sickle hemoglobin polymerization, voxelotor is approved by the US Food and Drug Administration (FDA) for the treatment of sickle cell disease in patients aged ≥4 years.3 The clinical benefit of voxelotor is shown to significantly improve anemia, but its effect on end-organ protection remains up for debate.

In the current study, Buckley and colleagues quantified the effects of voxelotor treatment in children with SCA using two non-invasive diffuse optical spectroscopies techniques: frequency-domain near-infrared spectroscopy (FDNIRS) and diffuse correlation spectroscopy (DCS).1 FDNIRS is an established technique used to assess regional blood volume and oxygen saturation and DCS is an arising technique used to determine an index of CBF (CBFi).

In the first study protocol, the estimates of CBFi were first validated against CBF measured by arterial spin-labeled magnetic resonance imaging (ASL-MRI) in a cohort of children with SCA aged 8 to 18 years old. The FDNIRS/DCS measurements of regional CBFi were collected within one hour of the MRI.

A total of 11 children consented to the validation of DCS against MRI, but three exclusions left 8 children for analysis. These patients were primarily female (75%) and had a median age of 14.1 years, with most receiving hydroxyurea therapy (88%). Upon analysis, the ASL-MRI measures of CBF were significantly positively associated with DCS measures of CBF (r2 = .651; P = .015).

In the second study protocol, a single-center, open-label pilot study was conducted in children with SCD aged 4 to 17 years. Eligible participants started open label voxelotor at 1500 mg or weight equivalent dose taken daily as a dispersible tablet or dissolvable powder. These participants were monitored before voxelotor treatment initiation and at 4, 8, and 12 weeks.

To assess voxelotor on cerebral hemodynamics, 11 participants consented and were screened for study eligibility. After a single failed screening and two withdrawn subjects, 8 patients (63% male; median age, 9 years) completed the planned study treatment and assessments. All subjects had HbSS and were on stable doses of hydroxyurea.

Upon analysis, compared with pre-treatment levels, OEF and CBFi were significantly decreased by week 4, with the decreases persisting to weeks 8 and 12 (both P < .05). Buckley and colleagues then measured the relationship between OEF, CBFi, and CBV and hemoglobin levels. They further observed a significant correlation between decreases in CBFi and increases in blood hemoglobin concentration (P = .024), while the correlation between OEF decreases and hemoglobin increases trended toward statistical significance (P = .129).

“Further investigations are warranted to validate these findings using alternative modalities and to determine if there is an association between these hemodynamic alterations and functional outcomes in patients receiving voxelotor therapy,” investigators wrote.


  1. Brothers RO, Turrentine KB, Akbar M, et al. The Influence of Voxelotor on Cerebral Blood Flow and Oxygen Extraction in Pediatric Sickle Cell Disease. Blood. Published online February 16, 2024. doi:10.1182/blood.2023022011
  2. Juttukonda MR, Lee CA, Patel NJ, et al. Differential cerebral hemometabolic responses to blood transfusions in adults and children with sickle cell anemia. J Magn Reson Imaging. 2019;49(2):466–477.
  3. Center for Drug Evaluation and Research. FDA approves drug to treat sickle cell disease in pediatric patients. U.S. Food and Drug Administration. December 17, 2021. Accessed February 20, 2024.